tbuckley/cabot-search huggingface dataset:
Identification and Characterization of Avoidable Hospital Admissions in Patients With Lung Cancer
Authors: Eric M. Lander, Xuanyi Li, Li-Ching Huang, Amanda S. Cass, Wade T. Iams, Emily A. Skotte, Jennifer G. Whisenant, Robert A. Ramirez, Sally J. York, Travis J. Osterman, Jennifer A. Lewis, Christine M. Lovly, Yu Shyr, Leora Horn
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: More than 50% of patients with lung cancer are admitted to the hospital while receiving treatment, which is a burden to patients and the healthcare system. This study characterizes the risk factors and outcomes of patients with lung cancer who were admitted to the hospital. Methods: A multidisciplinary oncology care team conducted a retrospective medical record review of patients with lung cancer admitted in 2018. Demographics, disease and admission characteristics, and end-of-life care utilization were recorded. Following a multidisciplinary consensus review process, admissions were determined to be either “avoidable” or “unavoidable.” Generalized estimating equation logistic regression models assessed risks and outcomes associated with avoidable admissions. Results: In all, 319 admissions for 188 patients with a median age of 66 years (IQR, 59–74 years) were included. Cancer-related symptoms accounted for 65% of hospitalizations. Common causes of unavoidable hospitalizations were unexpected disease progression causing symptoms, chronic obstructive pulmonary disease exacerbation, and infection. Of the 47 hospitalizations identified as avoidable (15%), the median overall survival was 1.6 months compared with 9.7 months (hazard ratio, 2.07; 95% CI, 1.34–3.19; P &lt;.001) for unavoidable hospitalizations. Significant reasons for avoidable admissions included cancer-related pain ( P =.02), hypervolemia ( P =.03), patient desire to initiate hospice services ( P =.01), and errors in medication reconciliation or distribution ( P &lt;.001). Errors in medication management caused 26% of the avoidable hospitalizations. Of admissions in patients receiving immunotherapy (n=102) or targeted therapy (n=44), 9% were due to adverse effects of treatment. Patients receiving immunotherapy and targeted therapy were at similar risk of avoidable hospitalizations compared with patients not receiving treatment ( P =.3 and P =.1, respectively). Conclusions: We found that 15% of hospitalizations among patients with lung cancer were potentially avoidable. Uncontrolled symptoms, delayed implementation of end-of-life care, and errors in medication reconciliation were associated with avoidable inpatient admissions. Symptom management tools, palliative care integration, and medication reconciliations may mitigate hospitalization risk.
Behavioral and brain responses to verbal stimuli reveal transient periods of cognitive integration of the external world during sleep
Authors: Başak Türker, Esteban Munoz Musat, Emma Chabani, Alexandrine Fonteix-Galet, Jean-Baptiste Maranci, Nicolas Wattiez, Pierre Pouget, Jacobo Sitt, Lionel Naccache, Isabelle Arnulf, Delphine Oudiette
Journal: Nature Neuroscience (2023)

Sleep has long been considered as a state of behavioral disconnection from the environment, without reactivity to external stimuli. Here we questioned this 'sleep disconnection' dogma by directly investigating behavioral responsiveness in 49 napping participants (27 with narcolepsy and 22 healthy volunteers) engaged in a lexical decision task. Participants were instructed to frown or smile depending on the stimulus type. We found accurate behavioral responses, visible via contractions of the corrugator or zygomatic muscles, in most sleep stages in both groups (except slow-wave sleep in healthy volunteers). Across sleep stages, responses occurred more frequently when stimuli were presented during high cognitive states than during low cognitive states, as indexed by prestimulus electroencephalography. Our findings suggest that transient windows of reactivity to external stimuli exist during bona fide sleep, even in healthy individuals. Such windows of reactivity could pave the way for real-time communication with sleepers to probe sleep-related mental and cognitive processes.
A single-cell genomic atlas for maturation of the human cerebellum during early childhood
Authors: Seth A. Ament, Marcia Cortes-Gutierrez, Brian R. Herb, Evelina Mocci, Carlo Colantuoni, Margaret M. McCarthy
Journal: Science Translational Medicine (2023)

Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to the risk of developing neurodevelopmental disorders. Here, using single-cell genomics of postmortem cerebellar brain samples, we characterized the postnatal development of cerebellar neurons and glia in 1- to 5-year-old children, comparing individuals who had died while experiencing inflammation with those who had died as a result of an accident. Our analyses revealed that inflammation and postnatal cerebellar maturation are associated with extensive, overlapping transcriptional changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons. Immunohistochemical analysis of a subset of these postmortem cerebellar samples revealed no change to Purkinje neuron soma size but evidence for increased activation of microglia in those children who had experienced inflammation. Maturation-associated and inflammation-associated gene expression changes included genes implicated in neurodevelopmental disorders. A gene regulatory network model integrating cell type-specific gene expression and chromatin accessibility identified seven temporally specific gene networks in Purkinje neurons and suggested that inflammation may be associated with the premature down-regulation of developmental gene expression programs.
BCL-xL Targeting to Induce Apoptosis and to Eliminate Chemotherapy-Induced Senescent Tumor Cells: From Navitoclax to Platelet-Sparing BCL-xL PROTACs
Authors: Anna Skwarska, Marina Konopleva
Journal: Cancer Research (2023)

Restoring apoptotic cell death is a critical goal for cancer therapy. One of the primary mechanisms by which cancer cells evade death and maintain survival in the face of stress signals is by overexpression of prosurvival B-cell lymphoma 2 (BCL2) family members such as BCL2, BCL-xL, and MCL1, which suppress the intrinsic (mitochondrial) pathway of apoptosis through complex protein and membrane interactions. While these antiapoptotic proteins have been validated as potent therapeutic targets, synthesis of their inhibitors remained challenging for decades mainly due to the presence of a difficult to target, highly hydrophobic groove on the surface. The groove serves as a binding site for the BH3 domain of corresponding proapoptotic partners, which leads to their sequestration and prevents apoptosis. In 2008, a Cancer Research article by Tse and colleagues, led by Dr. Steven Elmore from Abbott Laboratories, reported the discovery of the first orally bioavailable BCL2/BCL-xL inhibitor, navitoclax (ABT-263), marking the onset of an era of "BH3 mimetics" in cancer therapeutics and changing the therapeutic landscape especially for leukemia. Here, we reflect on how this landmark study fueled development of small-molecule BH3 mimetics like venetoclax and seek to indicate new strategies and future directions for improving the clinical activity of navitoclax for hematologic malignancies. See related article by Tse and colleagues, Cancer Res 2008;68:3421-3428.
Impact of face masks on the 6-minute walk distance in pulmonary hypertension patients during the COVID-19 pandemic: a prospective, randomised cross-over study
Authors: Max Wissmüller, Veit Wartner, Christopher Hohmann, Joana Adler, Tilmann Kramer, Martin Hellmich, Felix Gerhardt, Stephan Baldus, Stephan Rosenkranz
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>In patients with pulmonary hypertension, wearing face masks during the COVID-19 pandemic has significant impact on the 6-min walk distance, which should be considered for the interpretation of the risk status, and the overall evaluation of patients</b> https://bit.ly/3sL8guX
Cancer origin tracing and timing in two high-risk prostate cancers using multisample whole genome analysis: prospects for personalized medicine
Authors: Anssi Nurminen, Serafiina Jaatinen, Sinja Taavitsainen, Gunilla Högnäs, Tom Lesluyes, Naser Ansari-Pour, Teemu Tolonen, Kerstin Haase, Antti Koskenalho, Matti Kankainen, Juho Jasu, Hanna Rauhala, Jenni Kesäniemi, Tiia Nikupaavola, Paula Kujala, Irina Rinta-Kiikka, Jarno Riikonen, Antti Kaipia, Teemu Murtola, Teuvo L. Tammela, Tapio Visakorpi, Matti Nykter, David C. Wedge, Peter Van Loo, G. Steven Bova
Journal: Genome Medicine (2023)

Abstract Background Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question. Methods We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of 22 whole genome-sequenced sites (16 primary cancer foci and 6 lymph node metastatic) were analyzed using evolutionary reconstruction tools and spatio-evolutionary models. Probability models were used to trace spatial and chronological origins of the primary tumor and metastases, chart their genetic drivers, and distinguish metastatic and non-metastatic subclones. Results In patient GP5, CDK12 inactivation was among the first mutations, leading to a PrCa tandem duplicator phenotype and initiating the cancer around age 50, followed by rapid cancer evolution after age 57, and metastasis around age 59, 5 years prior to prostatectomy. In patient GP12, accelerated cancer progression was detected after age 54, and metastasis occurred around age 56, 3 years prior to prostatectomy. Multiple metastasis-originating events were identified in each patient and tracked anatomically. Metastasis from prostate to lymph nodes occurred strictly ipsilaterally in all 12 detected events. In this pilot, metastatic subclone content analysis appears to substantially enhance the identification of key drivers. Evolutionary analysis’ potential impact on therapy selection appears positive in these pilot cases. Conclusions PrCa evolutionary analysis allows tracking of anatomic site of origin, timing of cancer origin and spread, and distinction of metastatic-capable from non-metastatic subclones. This enables better identification of actionable targets for therapy. If extended to larger cohorts, it appears likely that similar analyses could add substantial biological insight and clinically relevant value.
Precise identification of cell states altered in disease using healthy single-cell references
Authors: Emma Dann, Ana-Maria Cujba, Amanda J. Oliver, Kerstin B. Meyer, Sarah A. Teichmann, John C. Marioni
Journal: Nature Genetics (2023)

Abstract Joint analysis of single-cell genomics data from diseased tissues and a healthy reference can reveal altered cell states. We investigate whether integrated collections of data from healthy individuals (cell atlases) are suitable references for disease-state identification and whether matched control samples are needed to minimize false discoveries. We demonstrate that using a reference atlas for latent space learning followed by differential analysis against matched controls leads to improved identification of disease-associated cells, especially with multiple perturbed cell types. Additionally, when an atlas is available, reducing control sample numbers does not increase false discovery rates. Jointly analyzing data from a COVID-19 cohort and a blood cell atlas, we improve detection of infection-related cell states linked to distinct clinical severities. Similarly, we studied disease states in pulmonary fibrosis using a healthy lung atlas, characterizing two distinct aberrant basal states. Our analysis provides guidelines for designing disease cohort studies and optimizing cell atlas use.
Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma
Authors: Liren Zhang, Jiali Xu, Suiqing Zhou, Feifan Yao, Ruizhi Zhang, Wenhua You, Jingjing Dai, Kai Yu, Yu Zhang, Tasiken Baheti, Liyong Pu, Jing Xu, Xiaofeng Qian, Chuanyong Zhang, Yongxiang Xia, Xinzheng Dai, Qing Li, Xuehao Wang
Journal: Journal of Hepatology (2023)
Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis
Authors: Peter J. Richardson, Daniel P. Smith, Alex de Giorgio, Xenia Snetkov, Joshua Almond-Thynne, Sara Cronin, Richard J. Mead, Christopher J. McDermott, Pamela J. Shaw
Journal: Translational Neurodegeneration (2023)

Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.
Screening for tuberculosis among migrants in Europe: harmonising approaches during a humanitarian crisis?
Authors: Saskia den Boon, Askar Yedilbayev
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>While there are advantages of standardising migrant TB screening programmes, especially during humanitarian crises such as the war in Ukraine, policies need to be based on evidence and may need to be specific to the local TB epidemiology and context</b> https://bit.ly/3ZfN3Wd
Consensus and controversies in the science of endophthalmitis management: Basic research and clinical perspectives
Authors: Taraprasad Das, Joveeta Joseph, Matthew P. Simunovic, Andrzej Grzybowski, Kuan-Jen Chen, Vivek Pravin Dave, Savitri Sharma, Patrick Staropoli, Harry Flynn
Journal: Progress in Retinal and Eye Research (2023)
Rheumatoid Arthritis and Risk of Lung Cancer: A Nationwide Cohort Study
Authors: Mi Hee Cho, Jong Ho Cho, Yeonghee Eun, Kyungdo Han, Jinhyoung Jung, In Young Cho, Jung Eun Yoo, Hyun Lee, Hyungjin Kim, Seong Yong Park, Dong Wook Shin
Journal: Journal of Thoracic Oncology (2023)
Machine Learning Improves Risk Stratification in Myelodysplastic Neoplasms: An Analysis of the Spanish Group of Myelodysplastic Syndromes
Authors: Adrian Mosquera Orgueira, Manuel Mateo Perez Encinas, Nicolas A Diaz Varela, Elvira Mora, Marina Díaz-Beyá, María Julia Montoro, Helena Pomares, Fernando Ramos, Mar Tormo, Andres Jerez, Josep F Nomdedeu, Carlos De Miguel Sanchez, Arenillas Leonor, Paula Cárcel, Maria Teresa Cedena Romero, Blanca Xicoy, Eugenia Rivero, Rafael Andres del Orbe Barreto, Maria Diez-Campelo, Luis E. Benlloch, Davide Crucitti, David Valcárcel
Journal: HemaSphere (2023)

Myelodysplastic neoplasms (MDS) are a heterogeneous group of hematological stem cell disorders characterized by dysplasia, cytopenias, and increased risk of acute leukemia. As prognosis differs widely between patients, and treatment options vary from observation to allogeneic stem cell transplantation, accurate and precise disease risk prognostication is critical for decision making. With this aim, we retrieved registry data from MDS patients from 90 Spanish institutions. A total of 7202 patients were included, which were divided into a training (80%) and a test (20%) set. A machine learning technique (random survival forests) was used to model overall survival (OS) and leukemia-free survival (LFS). The optimal model was based on 8 variables (age, gender, hemoglobin, leukocyte count, platelet count, neutrophil percentage, bone marrow blast, and cytogenetic risk group). This model achieved high accuracy in predicting OS (c-indexes; 0.759 and 0.776) and LFS (c-indexes; 0.812 and 0.845). Importantly, the model was superior to the revised International Prognostic Scoring System (IPSS-R) and the age-adjusted IPSS-R. This difference persisted in different age ranges and in all evaluated disease subgroups. Finally, we validated our results in an external cohort, confirming the superiority of the Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS) over the IPSS-R, and achieving a similar performance as the molecular IPSS. In conclusion, the AIPSS-MDS score is a new prognostic model based exclusively on traditional clinical, hematological, and cytogenetic variables. AIPSS-MDS has a high prognostic accuracy in predicting survival in MDS patients, outperforming other well-established risk-scoring systems.
The role of CD4<sup>+</sup> T cells in tumor and chronic viral immune responses
Authors: Luoyingzi Xie, Jingyi Fang, Juncheng Yu, Weinan Zhang, Zhiqiang He, Lilin Ye, Huaizhi Wang
Journal: MedComm (2023)

Abstract Immunotherapies are mainly aimed to promote a CD8 + T cell response rather than a CD4 + T cell response as cytotoxic T lymphocytes (CTLs) can directly kill target cells. Recently, CD4 + T cells have received more attention due to their diverse roles in tumors and chronic viral infections. In antitumor and antichronic viral responses, CD4 + T cells relay help signals through dendritic cells to indirectly regulate CD8 + T cell response, interact with B cells or macrophages to indirectly modulate humoral immunity or macrophage polarization, and inhibit tumor blood vessel formation. Additionally, CD4 + T cells can also exhibit direct cytotoxicity toward target cells. However, regulatory T cells exhibit immunosuppression and CD4 + T cells become exhausted, which promote tumor progression and chronic viral persistence. Finally, we also outline immunotherapies based on CD4 + T cells, including adoptive cell transfer, vaccines, and immune checkpoint blockade. Overall, this review summarizes diverse roles of CD4 + T cells in the antitumor or protumor and chronic viral responses, and also highlights the immunotherapies based on CD4 + T cells, giving a better understanding of their roles in tumors and chronic viral infections.
<i>LILAR</i>, a novel long noncoding RNA regulating autophagy in the liver tissues of endotoxemic mice through a competing endogenous RNA mechanism
Authors: Tian Tian, Shan Li, Haihua Luo, Yijing Li, Hanghang Chen, Ying Yang, Guangqin Chen, Bingyao Xie, Zhengzheng Yan, Zhenqi Wang, Lei Li, Yong Jiang
Journal: MedComm (2023)

Sepsis is an often-deadly complication of infection that can lead to multiple organ failure. Previous studies have demonstrated that autophagy has a protective effect on liver injury in sepsis. Here, we report a novel long noncoding RNA (lncRNA), named lipopolysaccharide (LPS)-induced liver autophagy regulator (
A de novo missense mutation in MPP2 confers an increased risk of Vogt–Koyanagi–Harada disease as shown by trio-based whole-exome sequencing
Authors: Xianyang Liu, Jiayu Meng, Xingyun Liao, Yusen Liu, Qian Zhou, Zongren Xu, Shuming Yin, Qingfeng Cao, Guannan Su, Siyuan He, Wanqian Li, Xiaotang Wang, Guoqing Wang, Dali Li, Peizeng Yang, Shengping Hou
Journal: Cellular and Molecular Immunology (2023)

Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1β, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.
CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition
Authors: Anja S. Swoboda, Vanessa C. Arfelli, Anna Danese, Roland Windisch, Paul Kerbs, Enric Redondo Monte, Johannes W. Bagnoli, Linping Chen-Wichmann, Alessandra Caroleo, Monica Cusan, Stefan Krebs, Helmut Blum, Michael Sterr, Wolfgang Enard, Tobias Herold, Maria Colomé-Tatché, Christian Wichmann, Philipp A. Greif
Journal: HemaSphere (2023)

Activating colony-stimulating factor-3 receptor gene (CSF3R) mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, and blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis, the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling, which can be exploited therapeutically.